Traumatic brain injury (TBI) and Alzheimer's disease (AD) can exhibit similar clinical and pathological features that suggest common neurodegenerative mechanisms. There is increasing evidence linking AD and TBI, including up-regulation of amyloid precursor protein (APP), and its toxic metabolite Abeta peptide, in head injured patients. The current proposal will determine 1) in controlled cortical impact (CCI) injury produces up-regulation of APP and Abeta protein levels; 2) the roles of the inflammatory cytokine IL1beta, NfkappaB, and caspases in this up- regulation; 3) how manipulations which alter IL1beta response, NfkappaB, or caspase activity affect metabolic processing of APP and the production of Abeta; and 4) the effects of these manipulations on apoptosis and behavioral outcomes. A novel approach will utilize 'humanized Abeta mice' that produce only human rather than rodent Abeta. This will enable use of available and extensively characterized antibodies specific for human APP and Abeta, and allow assessment of the toxicity of human Abeta in the in vivo rodent model. We will measure IL1beta, NfkappaB, caspases, APP mRNA and protein, and APP metabolites at various times after TBI in wild type and mutant mice. Experiments will dissect the mechanisms controlling APP metabolism and Abeta synthesis and toxicity, by examining the effects of IL1beta receptor antagonist, NfkappaB inhibitors, and both treatments together, as well as caspase inhibitors, on APP expression and metabolism after TBI. The humanized Abeta mouse will allow us to assess the toxicity of human Abeta in the animal model, assessing cognitive and motor performance outcome and apoptosis. Several techniques will be used, including ELISA, and northern and western blot, in situ hybridization, immunocytochemistry, and immunoprecipitation. We will parallel these studies clinically by examining the levels of APP and Abeta in CSF from human head injured patients, and in brain tissue from human patients whose injury required emergency surgical resections. Since TBI at the University of Pittsburgh is treated with 48 hours of hypothermia, we will also be able to assess hypothermia effects on CSF APP and Abeta, comparing them to normothermic samples previously collected. Preliminary evidence demonstrates that APP and Abeta are increased after TBI. The comprehensive studies proposed will provide valuable information regarding APP as a modulator in the post- injury recovery cascade and may suggest new therapeutic targets for both TBI and AD.